US7968302B2 - Detection of venous thromboembolic diseases by measurement of D-dimers and soluble fibrin levels - Google Patents

Detection of venous thromboembolic diseases by measurement of D-dimers and soluble fibrin levels Download PDF

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US7968302B2
US7968302B2 US12/299,169 US29916907A US7968302B2 US 7968302 B2 US7968302 B2 US 7968302B2 US 29916907 A US29916907 A US 29916907A US 7968302 B2 US7968302 B2 US 7968302B2
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fibrin
dimers
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degradation
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Bibi Shah Soltan Mirshahi
Jeannette Soria
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Diagnostica Stago SAS
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen

Definitions

  • the present application relates to a method and a test for detecting the activation of coagulation, in particular when it is linked to thromboembolic venous diseases, using an assay of D-dimers and assaying the soluble fibrin during a coagulation activation process in blood.
  • Fibrinolysis is the process of degradation of fibrin in the blood. Fibrinolysis is involved in a number of physiopathological processes and is triggered in situations when tissue plasminogen activator and plasminogen bind to fibrin, forming a ternary fibrin-plasminogen complex within which the t-PA has a high affinity for plasminogen, entraining the generation of plasmin, an enzyme which degrades fibrin into D-dimers. In the absence of fibrin, t-PA has little affinity for plasminogen, explaining the fact that circulating fibrin is not degraded.
  • D-dimer Degradation of fibrin, or fibrinolysis, leads to the formation of degradation products especially comprising “D-dimer” fragments.
  • Said D-dimers are associated with the E fragment from degradation of another fibrin monomer molecule forming the DDE complex, but even in that form, they are routinely termed D-dimers.
  • the fibrin undergoing the fibrinolysis process is formed by conversion of fibrinogen under the action of a coagulation enzyme, namely thrombin.
  • a coagulation enzyme namely thrombin.
  • the thrombin generated thus induces the formation of deposits of fibrin which will constitute the thrombus and the formation of soluble fibrin.
  • fibrin monomers which polymerize spontaneously into the form of a polymer by dint of hydrogen bonds established by interaction between A and B polymerization sites unmasked during liberation of the A and B fibrinopeptides and the a and b sites which are available at the ends of the gamma and beta chains respectively.
  • the fibrin polymer is then immediately stabilized by factor XIII(a).
  • Thrombin generation is much greater during in vitro tests than that which takes place in vivo. For this reason, the generation of fibrin monomers is much slower in the in vivo coagulation activation process than in that generated in vitro, which causes part of the monomers formed to polymerize to produce insoluble fibrin constituting the thrombus and another part of said monomers to react with fibrinogen in which the a and b sites are accessible, or with fibrinogen degradation products to produce soluble fibrin in which fibrin monomers are associated with fibrinogen.
  • Determining the concentration of soluble fibrin is important in order to witness the activation of coagulation in a patient. Said determination may be carried out using samples of blood or plasma obtained from a blood sample taken from a patient.
  • assaying soluble fibrin is a useful complement to assaying fibrinolysis degradation products, since soluble fibrin can detect coagulation activation which is under way while the concentration of D-dimers indicates degradation of a thrombus, even if the activation coagulation process is stopped.
  • the D-dimer plasma level is increased while the fibrin clot degrades in vivo. Hence, if the thrombus is present and undergoing degradation, the level of D-dimers is high, whether coagulation persists or is stopped. In contrast, the level of soluble fibrin is raised only if coagulation persists.
  • Determining the level of D-dimers in the sample is thus a reflection of the degradation of the thrombus which occurs in vivo, while determining the level of D-dimers obtained after exogenic addition of a specific fibrin thrombolytic agent represents the sum of the base D-dimers and the D-dimers deriving from degradation of soluble fibrin, also termed circulating fibrin.
  • Thromboembolic venous diseases principally comprise venous thromboses of the limbs and pulmonary embolism, the latter resulting from a complication of the first thromboses. Venous thromboses other than those of the limbs are also encountered, since all venous territories can undergo a thrombosis.
  • the renal veins and mesenteric veins can be cited in particular among those which are at the origin of pathologies.
  • the only D-dimers count measured until now lacks specificity and cannot allow one to conclude with certainty that an intra-vascular thrombus has formed, as the D-dimers present in the circulation may derive from the degradation of extra vascular fibrin deposits.
  • the D-dimers formed in situ may then pass into the circulation, hence producing a high level of circulating D-dimers.
  • the inventors have evaluated the pertinence of a diagnosis based on the D-dimers test in association with a rapid test for determining soluble fibrin which is representative of intra-vascular coagulation activation.
  • SDF soluble degradable fibrin
  • the invention concerns an in vitro method for diagnosing coagulation activation starting from a blood sample removed from a patient, comprising:
  • this risk exists if at least one of the calculated levels of said fibrin degradation product or SDF (D-dimers) is higher than the normal value and that risk is excluded when the calculated level of said degradation product of fibrin and the level of SDF are lower than the respective normal threshold values.
  • the reagent used to assay the degradation products is selected to measure a given group of degradation products.
  • antibodies with a predetermined specificity towards a particular type of fibrin degradation products are used.
  • the biological sample is preferably a biological liquid, for example a plasma or blood sample, or a puncture liquid, provided that the level of plasminogen in that liquid is identical to that of plasma.
  • a puncture liquid for example a plasma or blood sample, or a puncture liquid, provided that the level of plasminogen in that liquid is identical to that of plasma.
  • adding Glu-plasminogen must be considered so that the plasminogen concentration is close to that of plasma.
  • the plasminogen activator with a high affinity for fibrin used in the method for assaying soluble fibrin by generating specific degradation products may be selected from many compounds known to be plasminogen activators. However, certain of them degrade both fibrinogen and fibrin, such as streptokinase and urokinase. These compounds are not suitable for use in the method of the invention as they result in the degradation of fibrin giving rise to fibrinogen degradation products which interfere with those resulting from fibrin degradation.
  • Another group of plasminogen activators is constituted by compounds described as having a high specificity for degrading fibrin, compared with fibrinogen.
  • the method of the invention advantageously uses the specificity of this other group of compounds to carry it out and, for example, uses:
  • anti D-dimer antibodies are used to carry out the two assays (base D-dimers and D-dimers after action of specific fibrin plasminogen activator) of the method of the invention.
  • Said antibodies have been described in the prior art and are also commercially available, for example from Diagnostica Stago under the name “Lia-test” or under the name “Vidas” from Bio-Mérieux.
  • the assays of steps i) and ii) must use the same anti D-dimer antibody.
  • the conditions for use of the ELISA test from ASSERACHROM D-Di have advantageously been modified to shorten the test (15 min incubation with immobilized antibody and 15 minutes with antibody labeled with peroxidase).
  • the plasma is first incubated with a small quantity of thrombin for a predetermined period to allow the formation of soluble fibrin, without forming a clot of fibrin.
  • the coagulation process which has been triggered is then blocked by adding a thrombin inhibitor to prevent the reaction from continuing.
  • Hirudin or heparin for example, may be used as the inhibitor.
  • the in vitro diagnostic method also comprises treatment of a negative control sample, in particular a negative control plasma.
  • a negative control sample in particular a negative control plasma.
  • Evaluation of soluble fibrin in accordance with the present invention employs a first step for degradation of soluble fibrin by Pa-Fb sp, followed by measuring the specific degradation products resulting from the action of Pa-Fb sp.
  • the results of the method of the invention are obtained as rapidly as possible, while being representative of the quantity of soluble fibrin present in the sample.
  • the conditions for using the Pa-Fb sp must be determined so that degradation of the soluble fibrin is rapid and it is not accompanied by “contaminating” degradation of circulating plasmatic fibrinogen giving rise to degradation products interfering with those from soluble fibrin in the assay.
  • the doses of Pa-Fb sp to be used and the incubation period with the plasma are thus selected to induce an increase in the level of fibrin degradation products which is highest in the positive controls, and a practically zero increase in the negative controls (i.e. those which have not undergone treatment with a coagulation activator).
  • the Pa-Fb sp is selected from a group constituted by the activators cited above, namely: t-PA or its derivatives, VPA or its derivatives and staphylokinase or one of its mutants.
  • t-PA or staphylokinase is used, more preferably t-PA.
  • the final concentration of tested staphylokinase is in the range 1 to 12 ⁇ g/ml.
  • the final retained concentration is advantageously 10 ⁇ g/ml.
  • the incubation period may be modified and its variation is determined as a function of the nature and the concentration of the Pa-Fb sp used.
  • the t-PA is advantageously used in a final concentration range in the range 1 to 2.5 ⁇ g/ml.
  • the t-PA is used in a concentration of 2 ⁇ g/ml for an incubation period of 15 minutes at 37° C.
  • degradation of soluble fibrin by the plasminogen activator without degradation of fibrinogen may be blocked after degradation of the soluble fibrin by adding a plasmin inhibitor, for example aprotinin.
  • a plasmin inhibitor for example aprotinin.
  • Particular characteristics for using aprotinin or another plasmin inhibitor in equivalent manner are given in the examples.
  • the quantity of aprotinin used is, for example, equivalent to the quantity of plasminogen activator used.
  • the plasmin inhibitor is added after 15 minutes incubation at 37° C. with the plasminogen activator.
  • an anticoagulant such as a solution containing citric acid and sodium citrate may be added both to the assayed sample and to the control samples.
  • an anticoagulant such as a solution containing citric acid and sodium citrate may be added both to the assayed sample and to the control samples.
  • the quantities and mode of adding the citric acid and sodium citrate are indicated in the examples.
  • the diagnostic method described above is applied to investigating the formation of a venous thrombus.
  • the method is carried out for diagnostic exclusion of a deep venous thrombosis.
  • the diagnostic method is carried out for diagnostic exclusion of a pulmonary embolism.
  • the method is carried out on a blood sample taken from a patient prior to carrying out an anticoagulant treatment.
  • assaying soluble fibrin for the diagnostic exclusion of a venous thrombosis must be carried out before any anticoagulant treatment. If the patient undergoes treatment with anti-coagulants, the concentration of soluble fibrin reduces very quickly and reaches normal values. In treated patients, determination of the concentration of soluble fibrin in the plasma can only determine whether the anti-coagulant was effective.
  • the soluble fibrin assay is carried out using t-PA as the plasminogen activator.
  • FIGS. 1 and 2 respectively show a comparison of D-dimers and SDF in patients with suspected pulmonary embolism or with suspected deep venous thrombosis.
  • the black circles correspond to sick patients and the white circles to normal patients.
  • the line shows the upper limit of the normal value.
  • the positive control plasma was prepared using the following protocol:
  • the quantity of activator to be added to the test sample must be such that it induces the generation of a lot of D-dimers in the positive control plasma as obtained in example n o 1, with a non significant generation of D-dimers in a negative control plasma (control not treated with thrombin).
  • the selected dose of Pa-Fb sp is that which produces:
  • the D-dimers and soluble fibrin were assayed in 87 consecutive patients consulted in Emergency units with suspected venous thrombosis and/or pulmonary embolism and who had received no treatment. In these patients, an ultrasound investigation was carried out to diagnose deep venous thromboses; a scintography or a pulmonary angiograph was carried out to diagnose pulmonary embolism.
  • the D-dimers and soluble degradable fibrin (SDF) levels were determined before starting anti-coagulant treatment. It was shown that the sensitivity of the assay of soluble degradable fibrin was similar to that of the D-dimers assay (96% for D-dimers and for soluble degradable fibrin).
  • soluble degradable fibrin Rapid normalization of soluble degradable fibrin was observed in patients under anti-coagulant treatment at a curative dose. Once anti-coagulant treatment was instituted, the soluble fibrin level dropped. As a result, the soluble degradable fibrin can not be used as a diagnostic test in patients already treated with anti-coagulants. However, the soluble degradable fibrin may be useful for monitoring the anti-coagulant treatment. In conclusion, it is indicated that the level of soluble degradable fibrin in association with that of D-dimers is a useful clinical tool to predict or rule out pulmonary embolism and/or deep venous thrombosis.
  • Soluble fibrin is present during coagulation activation. Its increase is observed from the early stages of said activation.
  • the aim of the present study is to evaluate the potential use of a novel test based on determining the level of soluble degradable fibrin which is simple, rapid and sensitive and highly specific for plasmatic soluble fibrin polymers.
  • Soluble degradable fibrin was selected from markers for the generation of thrombin in vivo, such as fibrinopeptide A (FPA, half life 3 minutes (23) or the thrombin anti thrombin complex (TAT, half life 15 minutes (24)), because its measurement may be more sensitive as it is less sensitive to measurement anomalies.
  • FPA fibrinopeptide A
  • TAT thrombin anti thrombin complex
  • the diagnosis was confirmed by examining ultrasound compression; a diagnostic of pulmonary embolism was confirmed either by scintography or by pulmonary angiography.
  • the threshold value for the soluble degradable fibrin for a test which was considered to be positive was 300 ng/ml.
  • Plasma samples blood was collected on 0.13 M citrate (1 part of citrate for 9 parts blood). After centrifuging at 2500 g for 15 minutes, plasma was collected and frozen at ⁇ 20° C. until use.
  • the soluble degradable fibrin level was very high, as is the case with intra-vascular coagulation (DIVC), the soluble degradable fibrin may form an insoluble complex during the freezing and defrosting steps and as a result, it is recommended that this test be carried out with freshly collected plasma.
  • DIVC intra-vascular coagulation
  • the blood was obtained from healthy volunteers or from outpatients who had presented to Emergency units.
  • the patients who had received an anti-coagulant treatment were considered for monitoring only.
  • the population of patients consisted of consecutive patients presenting clinical signs of pulmonary embolism or deep venous thrombosis who had been diagnosed by ultrasound analysis of the compression of the proximal leg veins, by pulmonary scintography and by pulmonary angiography to verify the diagnosis.
  • the D-dimers were measured by agglutination of micro-particles of latex coated with monoclonal antibodies against D-dimers using the Lia-test (Diagnostica Stago) in an STA apparatus or by ELISA using VIDAS (bio-Mérieux).
  • the sample was diluted after the degradation step.
  • Adding aprotinin blocked the plasmin at a predetermined time, leading to the degradation of fibrin alone and not of fibrinogen.
  • the mean value was 80 ⁇ 106 ng/ml and of the 180 volunteers tested, 140 had an undetectable level of soluble degradable fibrin.
  • the threshold value taken for a positive test was 300 ng/ml.
  • D-dimers were normal ( ⁇ 500 ng/ml) in 2 patients (one of the group having a pulmonary embolism and the other in the group of patients presenting with deep venous thrombosis), while the levels of soluble degradable fibrin were >300 ng/ml.
  • the indices of pertinence (sensitivity, specificity, positive and negative predictive value) for the D-dimers, and the soluble degradable fibrin were calculated.
  • soluble degradable fibrin Rapid normalization of soluble degradable fibrin was observed in patients under non fractionated heparin or under low molecular weight heparin given in a curative dose. After day 1, the levels of soluble degradable fibrin were normal or at the upper limit of normal. Daily analysis of the levels showed that the soluble degradable fibrin remained within normal parameters during the treatment with heparin. In contrast, the levels of D-dimers reduced slowly and the levels did not reach normal levels during the treatment with heparin. In one patient, the soluble fibrin was further increased during therapeutic treatment, indicating an insufficient therapeutic effect.
  • This hypofibrinolysis may explain the 3% to 5% of cases of “false negatives” for D-dimers in patients presenting a constituted thrombosis.
  • the fibrin In determining the soluble degradable fibrin, the fibrin is readily accessible to fibrinolytic enzymes.
  • the fibrin of the thrombus when formed from fine and very tight fibrins, is less accessible to fibrinolytic enzymes, explaining the 3% to 5% of false negatives of D-dimers observed in thromboses.
  • the negative levels relative to soluble degradable fibrin were detected in 2 patients (one from the group presenting with pulmonary embolism and the other in the group of patients presenting with a deep venous thrombosis) while the level of D-dimers in these 2 patients was more than 500 ng/ml. This could suggest that the thrombogenicity is a non evolutive process since the activity of the thrombin is transitory.
  • the inventors have demonstrated that a combination of the two tests (soluble degradable fibrin and D-dimers) may be used to distinguish a diagnosis of pulmonary embolism from deep venous thrombosis in patients.
  • plasmatic D-dimers satisfy the criteria required for a diagnosis of pulmonary embolism and deep venous thrombosis as they are sensitive markers for thrombosis but lack specificity (26-35).
  • D-dimers cannot be used to carry out a positive diagnosis of thromboembolic venous diseases as the test is not sufficiently specific. However, when the level of D-dimers is normal, the diagnosis of thromboembolic disease can be made in 95% of patients.
  • soluble degradable fibrin in association with that of D-dimers may be considered to be a useful clinical tool for the diagnosis of deep venous thrombosis and pulmonary embolism and also of other thrombotic events. Further, it is suggested that soluble degradable fibrin may be useful in monitoring the effects of an anti-coagulation treatment.

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US12/299,169 2006-05-05 2007-05-03 Detection of venous thromboembolic diseases by measurement of D-dimers and soluble fibrin levels Active 2027-10-07 US7968302B2 (en)

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FR0604072A FR2900734B1 (fr) 2006-05-05 2006-05-05 Detection des maladies veineuses thromboemboliques par le dosage des d-dimeres et de la fibrine soluble
FR0604072 2006-05-05
PCT/FR2007/000764 WO2007128916A1 (fr) 2006-05-05 2007-05-03 Detection des maladies veineuses thromboemboliques par le dosage des d-dimeres et de la fibrine soluble

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JP5709425B2 (ja) 2010-07-27 2015-04-30 シスメックス株式会社 Ｄダイマー測定用試薬
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ES2687992T3 (es) 2013-07-30 2018-10-30 Industry-Academic Cooperation Foundation, Yonsei University Proteína de fusión saxatilina-Fc y utilización de la misma
CN106574922B (zh) * 2014-05-05 2020-06-05 美国血液技术公司 用于检测纤维蛋白溶解和纤溶亢进的方法学和试剂
CN104458367B (zh) * 2014-11-06 2019-03-26 上海长岛生物技术有限公司 一种d-二聚体和fdp复合质控品及其制备方法
JP6640494B2 (ja) * 2015-08-28 2020-02-05 シスメックス株式会社 血液検体分析方法、血液検体分析装置、及びコンピュータプログラム
FR3048001B1 (fr) * 2016-02-18 2018-02-09 Diagnostica Stago Methode de dosage des d-dimeres specifiques de la maladie thromboembolique veineuse
US11226342B2 (en) 2016-03-01 2022-01-18 Rowan University Methods utilizing D-dimer for diagnosis of periprosthetic joint infection
JP6667380B2 (ja) * 2016-06-17 2020-03-18 シスメックス株式会社 血液分析のための方法、血液分析装置、コンピュータプログラム、キャリブレータセット、及びキャリブレータセットの作製方法
CN108424960B (zh) * 2018-05-21 2021-08-17 山东中医药大学附属医院 一种LncRNA作为深静脉血栓形成诊断标志物的应用
CN108588217B (zh) * 2018-05-21 2021-08-17 山东中医药大学附属医院 一种LncRNA作为深静脉血栓形成诊断标志物的应用
RU2732246C1 (ru) * 2020-02-14 2020-09-14 Федеральное государственное бюджетное образовательное учреждение высшего образования «Национальный исследовательский Мордовский государственный университет им. Н.П. Огарёва» Способ прогнозирования тромбоэмболических послеоперационных осложнений
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CN113053534A (zh) * 2021-03-23 2021-06-29 张建楠 一种下肢深静脉血栓患者并发肺栓塞的预测分析方法

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